Described herein are biodegradable intraocular implants that provide for the extended release of bimatoprost in an amount that is effective for treating an ocular condition, particularly glaucoma and ocular hypertension, and conditions associated with glaucoma such as elevated intraocular pressure. The implants, which may be produced by an extrusion process, are sized and configured for placement in the anterior chamber of the eye where the implant can deliver the prostamide directly to the tissues regulating the production and outflow of aqueous humor. Importantly, the intraocular implants described here are designed not only to provide a patient with intraocular pressure-lowering levels of bimatoprost for a sustained period lasting for 2 months or more but are also sized to fit within the anterior chamber angle (also called the iridocorneal angle) of the eye without injuring the corneal endothelium and without obstructing vision. Though developed for the delivery of bimatoprost, implants in accordance with this invention may be useful for the sustained delivery of other prostamides as well. Methods for making and using these implants to treat an ocular condition are described.
Prostamides are potent ocular hypotensive agents useful in the treatment of a number of various ocular hypertensive conditions such as glaucoma, elevated intraocular pressure, and other ocular hypertensive episodes, including post-surgical and post-laser ocular hypertensive episodes (1, 4). They belong to an ever-expanding family of prostaglandin F2α C-1 amides (1-5). The biosynthesis and pharmacology of prostamides has been extensively described (1-3, 9). For example, naturally occurring prostamides, such as prostamide F2α, are biosynthesized from anandamide by a pathway exclusively involving COX-2. COX-1 is not involved (1, 2, 15). Other commercially available prostaglandin analogs include travoprost and latanoprost.

One prostamide that has found wide-spread use in ocular therapy is bimatoprost. Like other prostamides, bimatoprost exhibits no meaningful interaction with prostaglandin (PG) sensitive receptors (3, 10). Nevertheless, bimatoprost is a potent ocular anti-hypertensive agent and is highly effective for reducing elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension (1, 6-8). Bimatoprost is typically prescribed for use by patients in the form of an ophthalmic solution known by the tradename LUMIGAN®. In the usual course of therapy, Patients apply one drop of LUMIGAN® solution once daily to the surface of the affected eye(s) to reduce elevated intraocular pressure. Bimatoprost is believed to decrease intraocular pressure (IOP) by increasing aqueous humor outflow through the uveoscleral pathway (1, 3).
While highly effective for reducing intraocular pressure, the regular daily instillation of bimatoprost eye drops, nevertheless, requires daily management by the patient. It would be advantageous for some patients to have access to implantable drug delivery systems, such as intraocular implants, that are capable of delivering a therapeutically effective amount of bimatoprost to the eye at a consistent rate for an extended period to thereby reduce intraocular pressure in a hypertensive eye continuously for longer durations such as 2 months or more. A biodegradable intraocular implant, sized and configured for safe comfortable placement in the eye, and properly formulated to deliver a therapeutic amount of bimatoprost to tissues in the eye would effectively eliminate the need for patient compliance, since a patient would no longer need to apply daily eye drops, and by maintaining intraocular pressure at or below the levels typically obtained by topical application continuously for an extended period (such as 2 months or more), an intraocular implant may improve glaucoma therapy and lead to better therapeutic outcomes in some patients. Intraocular implants that include a prostamide component and a biodegradable polymer for the extended release of a prostamide such as bimatoprost, to treat an ocular condition such as glaucoma have been described (Ref 4, for example).
Glaucoma is generally a progressive disease of the eye characterized by progressive optic neuropathy with associated visual field loss. Glaucoma may be further associated with increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. Primary glaucoma in adults may be either open-angle glaucoma or acute or chronic angle-closure glaucoma. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract.
The underlying causes of primary glaucoma are not yet known. Risk factors include high or elevated intraocular pressure, advanced age, and family history. Increased or elevated intraocular pressure is due to the obstruction of aqueous humor outflow. In primary open-angle glaucoma, the anterior chamber and its anatomic structures appear normal, but drainage of the aqueous humor is impeded. In acute or chronic angle-closure glaucoma, the anterior chamber is shallow, the filtration angle is narrowed, and the iris may obstruct the trabecular meshwork at the entrance of the canal of Schlemm. Dilation of the pupil may push the root of the iris forward against the angle, and may produce pupillary block and thus precipitate an acute attack. Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of various degrees of severity.
Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber into the anterior chamber and subsequently, into the canal of Schlemm. Inflammatory disease of the anterior segment may prevent aqueous escape by causing complete posterior synechia in iris bombe and may obstruct movement of aqueous humor through the pupil leading to elevated intraocular pressure. Other common causes are intraocular tumors, enlarged cataracts, central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage. Considering all types together, glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptomatic for years before progressing to noticeable peripheral visual loss followed by central vision loss.
Glaucoma can be considered to be potentially both an anterior and posterior ocular condition because a clinical goal of glaucoma treatment can be not only to reduce elevated intraocular pressure because of obstructed aqueous humor outflow from the anterior chamber, but to also prevent the loss of or reduce the occurrence of loss of vision due to damage to or loss of retinal cells or optic nerve cells (i.e., ganglion cells) in the posterior of the eye (i.e. neuroprotection). Clinical trials have shown that reducing IOP can help retard the progression of glaucoma and consistent IOP reduction is associated with reduced risks of developing and progressing optic nerve damage (11-13).
Patient non-adherence to topical therapy is one of the major challenges to preventing vision loss due to glaucoma. Patients that take no medication are at the highest risk of vision loss from glaucoma; however, patients that intermittently take their medications are also at risk since IOP fluctuation has also been identified as possible risk factor for progression in some patients (14).
Accordingly, sustained-release drug delivery systems, such as biodegradable intraocular implants, that can continuously deliver a therapeutically effective amount of an anti-hypertensive drug such as bimatoprost directly into the anterior chamber of the eye may help reduce patient dependence on topical ocular anti-hypertensives or other anti-glaucoma medications to control intraocular pressure and manage symptoms associated with glaucoma.
The present invention provides for such drug delivery systems and offers additional improvements relative to some existing biodegradable intraocular implants. We have discovered a biodegradable implant formulation that swells less and biodegrades faster than some comparable intraocular implants, yet releases a therapeutically effective amount of bimatoprost at a nearly linear or constant rate for a sustained period (e.g., about 60 days), thereby providing patients with long-lasting relief from ocular hypertension and possibly protecting patients from some of the adverse effects caused by high or elevated intraocular pressure.
Such attributes are particularly valuable for implants placed in the anterior chamber of the eye (the fluid-filled space inside the eye between the iris and the innermost corneal surface, the corneal endothelium). Because most anterior chamber implants are more dense than aqueous humor, they tend to settle inferiorly into the angle of the anterior chamber (the junction between the front surface of the iris and the back surface of the cornea; also called the iridocorneal angle) after injection into the anterior chamber, where they may contact and possibly injure the corneal endothelium. Small, low-swell, rapidly degraded implants (i.e. implants that swell to less than 3 times (<3×) the initial size when placed in the anterior chamber), such as the ones we describe here, may reduce the risk of a patient developing corneal edema due to mechanical irritation of the corneal endothelium. In contrast, implants that swell greater than 3 fold (>3×) the initial size when placed in the anterior chamber have a higher risk of corneal endothelial cell touch and formation of corneal edema. Corneal edema can lead to cloudiness of normally transparent cornea and may result in vision loss if it extends to the central cornea. Furthermore, a small, low-swell implant that stays at a maximum swell for a shorter period before decreasing in size may enable physicians to safely administer the implant to a larger population of patients, including those with small or narrow anterior chamber angles. Rapid biodegradation of an implant after its drug load has been delivered means that a patient can receive one or more additional implants as needed as part of their continued therapy without having to worry about residual implants compromising their vision or comfort.
All such considerations, including the optimal size of the implant (e.g., length, diameter or width, and total mass) have been taken into account here in the development of the presently described implants.